Variation Of Cortisol Research Articles

Clinical Use of Reference Intervals Derived from Some CALIPER Studies Questioned

To the Editor: The availability of accurate and appropriate reference intervals is imperative for proper screening, diagnosis, and monitoring of disease. It is therefore with great interest that we read the recent reports (1, 2) by the CALIPER (Canadian Laboratory Initiative for Pediatric Reference Intervals)1 group. The efforts of the CALIPER project to provide these reference intervals for a diverse pediatric population is highly commendable, particularly in view of the substantial challenges of establishing them for this demographic. Apart from the rigors of selecting and collecting samples to establish reference intervals, the analytical quality of the data has to be ensured. It is with regard to these aspects of these studies that we would like to raise certain important concerns. Steroid concentrations are known to change substantially with the time of day when the blood sample is drawn. These samples were drawn over a 24-h period; thus, the within-participant variation in concentrations with time was not taken into account. This limitation is probably the most significant criticism of the CALIPER studies. With regard to the study of Bailey et al. (2), diurnal variation in cortisol is present in healthy children from an …

Workers’ psychological distress, depression, and burnout symptoms: associations with diurnal cortisol profiles

This study investigated whether self-reported psychological distress and depressive and burnout symptoms were associated with cortisol concentrations among workers. Day-shift workers (N=401) employed in 34 diverse workplaces in Canada participated. We administered well-validated questionnaires and collected salivary cortisol concentrations at five time points (awakening, 30 minutes after awakening, 14:00 hours, 16:00 hours, and bedtime) repeated three times a week (Saturday, Tuesday, Thursday) to capture work and non-workday variation. Multilevel regressions models estimated cortisol concentrations at different levels according to time of day, workers, and workplaces. After controlling for awakening time, sex, age, season of sampling, alcohol use, physical activity, psychotropic drugs use, health conditions, and body mass index, results revealed significant associations between psychological distress and depressive and burnout symptoms in relation to cortisol concentrations at different diurnal time points. Specifically, higher levels of psychological distress and depressive symptoms were associated with higher cortisol concentrations at awakening but not 30 minutes afterwards. Starting steadily from 14:00 hours until bedtime, levels of psychological distress and depressive and burnout symptoms were associated with lower cortisol concentrations. Significant cortisol variations were also found between workplaces. Sex did not moderate associations in secondary analyses. Distinct time points of diurnal cortisol variation were consistently, albeit modestly, associated with increased psychological distress and depressive and burnout symptoms. Our findings therefore link subjective psychometrics with objective biometrics. This research area could potentially lead to the development of refined screening tools that provide correspondence between diurnal cortisol and mental health.

Seasonal variations of basal cortisol and high stress response to captivity in Octodon degus, a mammalian model species

Across vertebrates, the hypothalamic–pituitary–adrenal axis is a conserved neuroendocrine network that responds to changing environments and involves the release of glucocorticoids into the blood. Few studies have been carried out concerning mammalian adrenal regulation in wild species either in the laboratory or field, and even fewer have been able to determine true glucocorticoid baselines. We studied the South-American caviomorph rodent Octodon degus, a diurnal and social mammal that has become an important species in the biological research. First, we determined the plasma cortisol baseline and the acute stress concentrations during the non-reproductive and mating seasons in free-living individuals. Second, using the same protocol we assessed the impact of long-term captivity on the adrenal function in wild-caught degus and degus born in laboratory. Third, we examined laboratory groups formed with degus taken from two distant natural populations; one of them originally occurs at the Andes Mountains in high altitude conditions. The data revealed seasonal modulation of basal cortisol in the wild associated with mating. In laboratory, degus presented higher cortisol stress responses, with greater magnitudes shown in degus born and reared in captivity. No differences between populations were found. The results suggest differential regulatory mechanisms between basal and stress-induced cortisol levels, and context dependence of cortisol modulation in a mammalian species.

The Postprandial Rise in Plasma Cortisol in Men Is Mediated by Macronutrient-Specific Stimulation of Adrenal and Extra-Adrenal Cortisol Production

Circadian variation is a fundamental characteristic of plasma glucocorticoids, with a postprandial rise in cortisol an important feature. The diurnal rhythm is presumed to reflect alterations in hypothalamic-pituitary-adrenal axis activity; however, cortisol is produced not only by the adrenal glands but also by regeneration from cortisone by the enzyme 11β-hydroxysteroid dehydrogenase type 1, mainly in liver and adipose tissue. We tested the contribution of peripheral cortisol regeneration to macronutrient-induced circadian variation of plasma cortisol in humans. This was a randomized, single-blinded, crossover study. The study was conducted at a hospital research facility. Eight normal-weight healthy men participated in the study. Subjects were given isocaloric energy isodense flavor-matched liquid meals composed of carbohydrate, protein, fat, or low-calorie placebo during infusion of the stable isotope tracer 9,11,12,12-[2H]4-cortisol. Plasma cortisol increased similarly after all macronutrient meals (by ∼90 nmol/L) compared with placebo. Carbohydrate stimulated adrenal secretion and extra-adrenal regeneration of cortisol to a similar degree. Protein and fat meals stimulated adrenal cortisol secretion to a greater degree than extra-adrenal cortisol regeneration. The increase in cortisol production by 11β-hydroxysteroid dehydrogenase type 1 was in proportion to the increase in insulin. The postprandial cortisol rise was not accounted for by decreased cortisol clearance. Food-induced circadian variation in plasma cortisol is mediated by adrenal secretion and extra-adrenal regeneration of cortisol. Given that the latter has the more potent effect on tissue cortisol concentrations and that effects on adrenal and extra-adrenal cortisol production are macronutrient specific, this novel mechanism may contribute to the physiological interplay between insulin and glucocorticoids and the contrasting effects of certain diets on postprandial metabolism.

Diel changes in plasma cortisol and effects of size and stress duration on the cortisol response in European sea bass (Dicentrarchus labrax)

European sea bass (Dicentrarchus labrax), one of the most economically important fish in Mediterranean mariculture, shows high basal cortisol concentrations compared with other teleosts. The present study aims (a) to identify cortisol diel variation in fish held under a 12L:12D cycle and minimum handling stress, and (b) to establish the effect of fish size and stressor duration on the cortisol response. The results indicate high intrapopulation variability in plasma cortisol and a significant diel fluctuation with a peak value at dusk (18h). Stressors of different intensity and/or duration affected the cortisol stress response in a differential manner according to fish size (and/or age). Maximum cortisol values in small-size fish were found at 1 and 2h post-stress, depending on the duration of the stressor, while at 0.5h post-stress in large fish regardless stress duration.

Relationship Status and Relationship Instability, but Not Dominance, Predict Individual Differences in Baseline Cortisol Levels

We investigated variation in baseline cortisol levels in relation to relationship status (single or in a relationship), relationship characteristics (length, stability, presence or absence of clear dominance), or individual attributes (dominant or subordinate status, relative physical attractiveness, relationship worries). Study participants were 77 men and 75 women aged between 18 and 38 years. Individuals in romantic relationships had lower cortisol levels than singles. Individuals of African ethnicity, however, showed the opposite pattern. Individuals who perceived their relationship to be highly unstable had higher cortisol levels. Aside from African-Americans, married individuals reported the lowest relationship instability and the lowest cortisol levels, followed by individuals in long-term relationships, and by individuals in short-term relationships. The presence or absence of clear dominance in the relationship, dominance status, or relationship worries did not affect cortisol levels. Therefore relationship status and relationship instability were better predictors of variation in cortisol (presumably through stress-related mechanisms) than individual attributes.

Using a biokinetic model to quantify and optimize cortisol measurements for acute and chronic environmental stress exposure during pregnancy

To fully understand the potentially harmful effects of prenatal stress exposure impacts, it is necessary to quantify long-term and episodic stress exposure during pregnancy. There is a strong body of research relating psychological stress to elevated cortisol levels in biomarkers. Recently, maternal hair has been used to measure cortisol levels, and provides the unique opportunity to assess stress exposure throughout gestation. Understanding how cortisol in the hair is related to more common biomarkers, such as, blood, saliva and urine is currently lacking. Therefore, we developed a biokinetic model to quantify the relationships between hair, blood, saliva and urine cortisol concentrations using published literature values. Hair concentrations were used to retrospectively predict peaks in blood and saliva concentrations over days and months. Simulations showed realistic values in all compartments when results were compared with published literature. We also showed that the significant variability of cortisol in blood leads to a weak relationship between long-term and episodic measurements of stress. To our knowledge, this is the first integrative biokinetic cortisol model for blood, urine, hair and saliva. As such, it makes an important contribution to our understanding of cortisol as a biomarker and will be useful for future epidemiological studies.

Seasonal pattern of salivary cortisol secretion in the greater one-horned rhino(Rhinoceros unicornis)

AbstractThe Indian rhinoceros or greater one-horned rhino(Rhinoceros unicornis)is listed as vulnerable by the IUCN Red List of Threatened Species and, therefore, captive individuals have been subject to the European Endangered Species Programme since 1990. Enhancement of welfare is key in ensuring the breeding success of this species in captivity. Salivary cortisol has been recently used to assess welfare of captive and free-ranging animals. Nevertheless, rhythms of cortisol secretion may fluctuate throughout the year and therefore, knowledge of the circannual pattern of cortisol secretion is essential to evaluate the physiological significance of seasonal variations of cortisol levels as an indicator of stress in animals. Here, we analyse monthly differences in cortisol secretion in two Indian rhinoceros. Saliva samples of two rhinoceros were collected and analysed by radioimmunoassay for the period of one year to determine cortisol concentrations. We found a seasonal pattern of salivary cortisol secretion. The highest cortisol concentrations were found in August and decreased until reaching a nadir in January. Cortisol concentrations in these two animals showed a correlation with temperature and visitor numbers but it is not possible to draw conclusions from this study as to whether the variation in cortisol was due to these or other factors.

HPA axis genetic variation, cortisol and psychosis in major depression.

Genetic variation underlying hypothalamic pituitary adrenal (HPA) axis over-activity in healthy controls and patients with severe forms of major depression has not been well explored but could explain risk for cortisol dysregulation.95 participants were studied: 40 patients with psychotic major depression (PMD); 26 patients with nonpsychotic major depression (NPMD); and 29 healthy controls (HC). Collection of genetic material was added one third of the way into a larger study on cortisol, cognition, and psychosis in major depression. Subjects were assessed using the Brief Psychiatric Rating Scale, the Hamilton Depression Rating Scale and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. Blood was collected hourly for determination of cortisol from 6pm to 9am and for the assessment of alleles for 6 genes involved in HPA Axis regulation.Two of the 6 genes contributed significantly to cortisol levels, psychosis measures or depression severity. After accounting for age, depression, and psychosis, and medication status, only allelic variation for the glucocorticoid receptor gene (GR) accounted for significant variance for mean cortisol levels from 6pm to 1am (r2=.317) and from 1am to 9am (r2=.194). Interestingly, neither depression severity nor psychosis predicted cortisol variance. In addition, GR and corticotropin-releasing hormone receptor 1 (CRH-R1) contributed significantly to psychosis measures and CRH-R1 contributed significantly to depression severity rating.

The effects of season, daylight saving and time of sunrise on serum cortisol in a large population

Cortisol is critical for maintenance of health and homeostasis and factors affecting cortisol levels are of clinical importance. There is conflicting information about the effects of season on morning cortisol and little information on the effects of sunlight on population cortisol assessment. The aim of this study was to assess whether changes in median serum cortisol occurred in a population in conjunction with changing seasons, daylight saving time (DST) or time of sunrise. We analysed serum cortisol results (n = 27 569) from a single large laboratory over a 13-year period. Subjects with confounding medications or medical conditions were excluded and data analysed in 15-minute intervals. We assessed the influence of traditional seasons, seasons determined by equinox/solstice, DST and time of sunrise on median cortisol. The median time of cortisol collection did not vary significantly between seasons. Using traditional seasons, median cortisol was lowest in summer (386 nmol/L) and spring (384 nmol/L) with higher cortisol in autumn (406 nmol/L) and winter (414 nmol/L). Median cortisol was lowest in the summer solstice quarter with significant comparative increases in the spring equinox quarter (3.1%), the autumn equinox quarter (4.5%) and the winter solstice quarter (8.6%). When cortisol was modelled against time, with adjustment for actual sunrise time on day of collection, for each hour delay in sunrise there was a 4.8% increase in median cortisol (95% CI: 3.9–5.7%). In modelling to explain the variation in cortisol over the morning, sunrise time was better than season in explaining seasonal effects. A subtle cyclic pattern in median cortisol also occurred throughout the months of the year. A 3-year trial of DST allowed comparison of cortisol in DST and non DST periods, when clock time differed by one hour. There was modest evidence of a difference in acrophase between DST and non DST cortisol (p = 0.038), with DST peak cortisol estimated to occur 58 minutes later than non-DST peak. In summary, we found that time of sunrise and time of cortisol collection were the most important factors influencing median cortisol. For each hour later that the sun rose there was an almost 5% increase in median cortisol. There was significant seasonal variability with lowest cortisol noted in summer coinciding with the earliest sunrise time. This is an important finding which is consistent with the understanding that light is the major zeitgeber in entrainment of the human circadian cortisol rhythm. Our data suggest this rhythm is resistant to the arbitrary changes in clock time with daylight saving.

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What's in this issue?

Hypothalamic-Pituitary-Adrenal Axis Recovery Following Prolonged Prednisolone Therapy in Infants

The duration of hypothalamic-pituitary-adrenal (HPA) axis suppression after glucocorticoid treatment is uncertain. We aimed to determine the duration of HPA axis suppression in prednisolone-treated infants and the age at which circadian variation in salivary cortisol is established in healthy infants. Before the adoption of propranolol treatment by the Vascular Birthmarks Clinic, 12 infants with infantile hemangioma received high-dose prednisolone for 12 to 25 weeks' duration, weaned over 4 to 6 weeks, and ceased at age 21 to 31 weeks. Parents collected serial salivary samples at two time points per day (before first and last feed) until circadian variation in salivary cortisol (measured by radioimmunoassay) was observed, when a confirmatory 1 μg Synacthen test was performed. Ten healthy control infants had serial salivary cortisol measurements to determine the age at which circadian variation is established. We defined circadian variation as evening salivary cortisol <50% of the early morning level on two consecutive sampling weeks. Circadian variation appeared within 6 weeks (median 2.7, range 1.4-5.4) of prednisolone cessation. All confirmatory Synacthen tests were normal (peak serum cortisol >600 nmol/L) and were performed within 12 weeks of prednisolone cessation. Healthy controls developed circadian variation at median 16 weeks of age (range 8-24). HPA recovery occurred within 6 to 12 weeks, shorter than empirical recommendations, to give stress cover for 6 to 12 months. Reduced duration of stress-cover precautions may reduce parental anxiety and side effects from unnecessary glucocorticoid use. Healthy control infants established circadian variation in salivary cortisol between 2 and 6 months of age.

Influence of adrenocorticotrophin hormone challenge and external factors (age, sex, and body region) on hair cortisol concentration in Canada lynx (Lynx canadensis)

Land use changes are a significant factor influencing the decline of felid populations. However, additional research is needed to better understand how these factors influence populations in the wild. Hormone analysis can provide valuable information on the basic physiology and overall health of an animal, and enzyme immunoassays (EIA) are generally used for hair hormone analysis but must first be validated for the substrate of choice and species of interest. To date, hormone assays from hair have not been validated for Felidae, despite that the method holds considerable promise for non-invasive sampling of free-ranging animals. We sought to: (1) evaluate whether increased adrenocorticotrophin hormone (ACTH) during the period of hair growth results in elevated hair cortisol; (2) validate the enzyme immunoassay used; and (3) identify any variations in hair cortisol between age, sex and body regions, using Canada lynx. We quantified hair cortisol concentrations in captive animals through an ACTH challenge and collected samples from legally harvested lynx to compare variability between body regions. An EIA was validated for the analysis of hair cortisol. Lynx (n=3) had a qualitative increase in hair cortisol concentration following an ACTH challenge in captive animals (20IU/kg of body weight weekly for 5weeks), thereby supporting the use of an EIA to quantify cortisol values in hair. Based on our analysis of sampled lynx pelts, we found that hair cortisol did not vary between age and sex, but varied within the foot/leg region to a greater extent than between individuals. We recommend that future studies identify a standardized location for hair cortisol sampling.

Circulation Research Thematic Synopsis Diabetes and Obesity

<i>Circulation Research</i> Thematic Synopsis Diabetes and Obesity

Disentangling the effects of genetic, prenatal and parenting influences on children’s cortisol variability

Developmental plasticity models hypothesize the role of genetic and prenatal environmental influences on the development of the hypothalamic–pituitary–adrenal (HPA) axis and highlight that genes and the prenatal environment may moderate early postnatal environmental influences on HPA functioning. This article examines the interplay of genetic, prenatal and parenting influences across the first 4.5 years of life on a novel index of children’s cortisol variability. Repeated measures data were obtained from 134 adoption-linked families, adopted children and both their adoptive parents and birth mothers, who participated in a longitudinal, prospective US domestic adoption study. Genetic and prenatal influences moderated associations between inconsistency in overreactive parenting from child age 9 months to 4.5 years and children’s cortisol variability at 4.5 years differently for mothers and fathers. Among children whose birth mothers had high morning cortisol, adoptive fathers’ inconsistent overreactive parenting predicted higher cortisol variability, whereas among children with low birth mother morning cortisol adoptive fathers’ inconsistent overreactive parenting predicted lower cortisol variability. Among children who experienced high levels of prenatal risk, adoptive mothers’ inconsistent overreactive parenting predicted lower cortisol variability and adoptive fathers’ inconsistent overreactive parenting predicted higher cortisol variability, whereas among children who experienced low levels of prenatal risk there were no associations between inconsistent overreactive parenting and children’s cortisol variability. Findings supported developmental plasticity models and uncovered novel developmental, gene × environment and prenatal × environment influences on children’s cortisol functioning.

Cortisol, alpha amylase, and daily stressors in spouses of persons with mild cognitive impairment.

This study examines the effects of daily primary objective stressors (behavioral problems exhibited by persons with mild cognitive impairment) and subjective stressors (unpleasant marital interactions) on the diurnal cortisol pattern and the diurnal pattern of salivary alpha-amylase (sAA) of spousal care partners. Thirty spouse care partners (age 59-85 years) participated in a 7-day diary study and submitted saliva samples on 4 consecutive study days, totaling 406 valid samples. Results from multilevel models revealed that daily objective stressors were associated with elevated cortisol levels and a flatter slope but were not associated with sAA activity. Conversely, unpleasant marital interactions were associated with flatter sAA slopes but not associated with cortisol activity. Furthermore, daily levels of sAA moderated variations in cortisol in the presence of a primary objective stressor. The utility of our research has implications for advancing scientific understanding of biosocial processes and the development of stress prevention and intervention strategies.

Sputum interleukin-6, tumor necrosis factor-α and Salivary cortisol as new biomarkers of depression in lung cancer patients

Depression is common among lung cancer patients. Increasing evidence has suggested that hypothalamic-pituitary-adrenal (HPA) axis and pro-inflammatory cytokines may play a key role in the pathophysiology of depression as well as cancer. This pilot study investigated the efficacy of sputum interleukin (IL)-6, tumor necrosis factor (TNF)-α and salivary cortisol as new markers to support the diagnosis of depression in lung cancer patients. The diurnal rhythms of sputum IL-6, sputum TNF-α and salivary cortisol were measured in lung cancer patients with and without depression as well as depressed controls and healthy controls. The area under the diurnal variation curves (AUC) over the 24h time course and relative diurnal variation (VAR) were calculated. Receiver operating characteristic (ROC) analysis was performed. Patients with co-morbid depression and lung cancer showed highest level of sputum IL-6 AUC, sputum TNF-α AUC and lowest level of cortisol VAR (P<0.001). As a biomarker for depression, salivary cortisol VAR demonstrated an optimal cutoff point at 77.8% (AUC=0.94; 95% CI, 0.85-0.98), which is associated with a sensitivity of 82.1% and a specificity of 96.0%. Sputum IL-6 AUC demonstrated a sensitivity of 74.4% and a specificity of 92.0% (AUC=0.81; 95% CI, 0.69-0.90). These findings suggested that higher 24h overall levels of sputum IL-6, TNF-α and flattened diurnal salivary cortisol slopes were associated with depression in lung cancer patients. Sputum IL-6 AUC and salivary cortisol VAR performed best as biomarkers in the diagnosis of depression in lung cancer patients.

Salivary Cortisol and Cold Pain Sensitivity in Female Twins

There is a dearth of knowledge about the link between cortisol and pain sensitivity. We examined the association of salivary cortisol with indices of cold pain sensitivity in 198 female twins and explored the role of familial confounding. Three-day saliva samples were collected for cortisol levels and a cold pressor test was used to collect pain ratings and time to threshold and tolerance. Linear regression modeling with generalized estimating equations examined the overall and within-pair associations. Lower diurnal variation of cortisol was associated with higher pain ratings at threshold (p = 0.02) and tolerance (p < 0.01). The relationship of diurnal variation with pain ratings at threshold and tolerance was minimally influenced by familial factors (i.e., genetics and common environment). Understanding the genetic and non-genetic mechanisms underlying the link between HPA axis dysregulation and pain sensitivity may help to prevent chronic pain development and maintenance.

Maternal sensitivity and infant and mother adrenocortical function across challenges

Findings regarding associations between maternal sensitivity and infant and mother adrenocortical function have been inconsistent. Nor have studies addressed the issue of intra-individual, between-challenge cortisol variability in the context of maternal sensitivity. In this study, we combine several design features aimed at sensitizing analyses to these issues. Cortisol secretion of 297 infants and their mothers was assessed in response to different challenges at 16 and 17 months. Extensive, structured observations of maternal sensitivity were conducted at infant age 16 months. Data were analyzed with multilevel modeling using an actor-partner interdependence model. We found that maternal sensitivity was related to infant, but not maternal, cortisol levels and also to infant-mother cortisol attunement. Infants of more sensitive mothers, as compared to infants of less sensitive mothers, showed greater cortisol variability across challenges, with relatively steep cortisol decreases and increases, depending on challenge. Mother and infant cortisol levels were highly correlated and this attunement was higher among dyads with more sensitive mothers than among dyads with less sensitive mothers. The results show nuanced attunement in a low-risk sample, with the infants of higher sensitivity mothers showing greater intra-individual variability across challenges. High cortisol response variability across challenges may simultaneously permit adaptation to threat and protect the infant from overexposure to corticosteroids.

Sexual Dysfunctions in Men Affected by Autoimmune Addison's Disease Before and After Short-Term Gluco- and Mineralocorticoid Replacement Therapy

There is evidence suggesting that autoimmune Addison's disease (AD) could be associated with sexual dysfunctions probably caused by gluco- and mineralocorticoid deficiency; however, no study has yet treated this subject in males. To evaluate male sexuality and psychological correlates in autoimmune AD before and after gluco- and mineralocorticoid replacement therapy. Twelve subjects with a first diagnosis of autoimmune AD were studied before (baseline) and 2 months after (recovery phase) initiating hormone replacement therapy. Erectile function (EF), orgasmic function (OF), sexual desire (SD), intercourse satisfaction (IS), overall satisfaction (OS), depression, and anxiety were studied using a number of questionnaires (International Index of Erectile Function, Beck Depression Inventory, and Spielberger State-Trait Anxiety Inventory); clinical, biochemical, and hormone data were included in the analysis. At baseline, low values were found for EF, OF, SD, IS, and OS and high values for depression and anxiety; all of these parameters improved significantly in the recovery phase compared with baseline. EF variation between the two phases correlated significantly and positively with the variation of serum cortisol, urinary free cortisol, systolic blood pressure, and diastolic blood pressure and inversely with that of upright plasma renin activity. Multiple linear regression analysis using EF variation as dependent variable confirmed the relationship of the latter with variation of serum cortisol, urinary free cortisol, and upright plasma renin activity but not with variation of systolic and diastolic blood pressure. Our study showed that onset of autoimmune AD in males is associated with a number of sexual dysfunctions, all reversible after initiating replacement hormone therapy; cortisol and aldosterone deficiency seems to play an important role in the genesis of erectile dysfunction although the mechanism of their activity is not clear.